The studies proposed in PROJECT A seek to develop scientific tools to characterize molecular mechanisms regulating balance between defense mediated by the immune system and establishment or maintenance of infections. The PI is the chairperson of the Department of Molecular Microbiology and Immunology (MMI), Christine A. Biron. The experiments proposed are from Assistant Professors in the Department, Walter J. Altwood, Andrew G. Campbell, Laurent Brossay, and George Yap. MMI is the youngest of the basic science departments at Brown University. It is developing a focus on the programmatic theme presented in this application, and the overall general research area of innate mechanisms in resistance to microbial infections. The MMI group's interest compliment research in a number of clinical departments. All of the junior investigators in this project will benefit from the efforts proposed for faculty and research development in the administrative core. The studies planned will take advantage of and dependent upon the research core facilities proposed including the transgenic mouse, flow cytometric, and confocal/imaging laboratories. The work will be advanced in the following specific aims: 1. Establishment of Approaches to Identify Early Events in Infection of B cells by JV Virus, an Agent Associated with Neuropathology, 2. Characterization of the Structure and Function of the Hepatitis B Virus RNase H Enzyme Using a Novel Molecular Approach, 3. Development of a System to Critically Test the Function of NK T Cells in Responses to Infectious Agents, and 4. Construction of a System to Characterize Tissue-Specific Regulation of MHC Class I Expression as a Determinant of Latency and Immunopathology in Toxoplasma. The products and results of these experiments promise to advance understanding of basic molecular events contributing to health and disease during infections. Moreover, they will enhance Rhode Island's competitiveness for further national research support by developing these junior investigators and by providing them with unique new experimental tools for use in other advancing and developing projects characterizing the factors regulating and therapeutic tools for enhancing defense against infections.